Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the expression of the metastases-associated gene MTA1 correlates with tumor metastases, its role in regulating type IV collagenase expression is unknown. Enforced MTA1 expression in HT1080 cells reduced basal and 12-myristate 13-acetate-induced 92-kDa type IV collagenase (MMP-9) protein/mRNA levels. DNase I hypersensitivity and PstI accessibility assays revealed multiple regions of the MMP-9 promoter (-650/-450 and -120/+1), showing reduced hypersensitivity in the MTA1-expressing cells. Chromatin immunoprecipitation assays demonstrated MTA1 binding to the distal region, which spans several regulatory cis elements. Co-immunoprecipitation and chromatin immunoprecipitation assay experiments revealed histone deacetylase 2 (HDAC2)-MTA1 protein-protein interactions and the MTA1-dependent recruitment of HDAC2 to the distal MMP-9 promoter region, yielding diminished histone H3/H4 acetylation. However, HDAC2 binding and H3/H4 acetylation at the proximal MMP-9 region were unaffected by MTA1 expression. Furthermore, trichostatin treatment only partially relieved MTA1-repressed MMP-9 expression, indicating a HDAC-insensitive component possibly involv ing the nucleosome-remodeling Mi2 activity, which was recruited to the promoter by MTA1. In summary, (a) MMP-9 adds to a short list of MTA1-regulated genes, which so far only includes c-myc and pS2, and (b) MTA1 binds to the MMP-9 promoter, thereby repressing expression of this type IV collagenase via histone-dependent and independent mechanisms.
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PMID:Repression of 92-kDa type IV collagenase expression by MTA1 is mediated through direct interactions with the promoter via a mechanism, which is both dependent on and independent of histone deacetylation. 1243 81

Multiple myeloma (MM) is an incurable plasma cell cancer, localized in the bone marrow (BM). The mechanisms used by these cells to (re-)enter this organ remain largely unknown. Recently, we reported that both CD45+ and CD45- myeloma cells home to the BM and induce myeloma disease. In this work, we investigated the underlying mechanisms involved in the homing of CD45+ and CD45- myeloma cells in the experimental 5T2MM and 5T33MM murine models. In vivo tracing of flow cytometric sorted and radioactively labeled CD45 subsets revealed a reduced homing of the CD45- 5TMM cells to the BM as compared to the CD45+ 5TMM cells. Migration assays demonstrated an impaired chemotaxis towards BM endothelial cell conditioned medium, BM stromal cell conditioned medium and towards the basement membrane component laminin-1 of the CD45- 5TMM cells compared to the CD45+ subset. Matrix metalloproteinase-9 (MMP-9) and urokinase type plasminogen activator (uPA) are key extracellular matrix proteases involved in the invasion of cancer cells. Inhibitor and antibody blocking experiments demonstrated the involvement of both in the invasion of the 5TMM cells. CD45- 5TMM cells had a low secretion of MMP-9 and (for the non-aggressive line 5T2MM only) a low cell surface expression of uPA receptor, as revealed by gelatin zymography and flow cytometric analysis, respectively. Accordingly, the synthetic basement membrane invasive capacity of the CD45- 5TMM subpopulations was also impaired. Our results indicate that CD45+ and CD45- 5T myeloma cells have a differential BM homing attributable to differential migratory and invasive capacities.
Clin Exp Metastasis 2002
PMID:Mechanisms involved in the differential bone marrow homing of CD45 subsets in 5T murine models of myeloma. 1249 87

The main focus of the Symposium was the fact that cell types of the innate and adaptive immune systems can have tumor-favoring as well as tumor antagonistic effects, both in a preventive and therapeutic mode. It was shown that macrophages (Mphi) and dendritic cells within a tumor exert tumor-favoring effects through the action of certain cytokines. Inflammatory reactions could favor the onset and growth of tumors. Dual immune functions were shown with CD4+ T cells and certain matrix metalloproteinase (MMP) activities favoring tumor progression and CD8+ T cells and certain heat shock proteins having antitumor action. Lack of antitumor action despite positive immune stimulation was also shown to depend on the existence of barriers to tumor infiltration by lymphocytes; remodeling of vasculature, e.g., by IFNgamma-induced cytokines like MIG and IPIO, reversed this type of impediment. Certain CXC cytokines increased tumor progression, whereas others, particularly those induced by IFNgamma, had the opposite effect; stromal-derived factor-1 and its receptor CXCR4 affected tumor propensity to metastasize in certain organs. Stromal-derived factor-1 induced MMP9, which in turn regulated the bioavailability of vascular endothelial growth factor and the cascade of its tumor-favoring effects, whereas granulocyte colony-stimulating factor decreased MMP9 and the consequences of its action. The effects of certain proinflammatory cytokines and vascular endothelial growth factor functions in angiogenesis and lymphoangiogenesis were also discussed. The favoring effects of fever-like thermal stress on the function of molecules instrumental in lymphoid cell adhesion to vessels and infiltration into sites of immune actions were described. The mechanisms involved in the development of immune memory and those conditioning Type I and CTL responses were also discussed. A number of presentations were concerned with laboratory studies aimed at developing clinical regimens with potential activity in the prevention or treatment of cancer. Prevention of Her2/neu breast cancer in transgenic mice was achieved by suitable regimens with IL12 combined with vaccines, including DNA-based vaccines administered in conjunction with electroporation. Vaccination with shared tumor antigen MUCI or cyclin B was discussed, and its clinical translation was described. The prevention of TRAMP prostate tumor in transgenic mice by anti-CTLA4 antibody plus vaccine was described, as was the translation of these regimens to the clinics. Clinical successes in melanoma patients using antimelanoma antigen antibodies in a therapeutic mode and precautions to be exerted in evaluating in vivo immune responses based on in vitro assays were emphasized. The symposium was concluded with an overall discussion focused on basic questions related to the capability of immunity to exert tumor-favoring or antitumor effects depending on conditions determined by both tumor and host functions.
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PMID:Fourteenth Annual Pezcoller Symposium: the novel dichotomy of immune interactions with tumors. 1278 11

Inhibitors of matrix metalloproteinases (MMPs) were developed as anticancer agents based on the observation that MMPs facilitate local tumor spread and metastasis by promoting matrix degradation and cell migration. Unfortunately, these inhibitors were unsuccessful in the clinical treatment of several cancers, including lung cancer. A possible reason contributing to their failure is that MMP activity is critical for the generation of inhibitors of tumor angiogenesis, including angiostatin. Thus, MMPs might play opposing roles in tumor vascularization and invasion. To determine which effect of elevated MMP levels dominates in the progression of metastatic cancer, experimental lung metastasis assays were performed in integrin alpha1-null mice, a genetic model for increased plasma levels of MMP9 and MMP9-generated angiostatin (Pozzi et al., Proc. Natl. Acad. Sci. USA 2000;97:2202-7). We show that while the number of lung colonies in integrin alpha1-null mice was significantly increased compared to their wild-type counterparts, tumor volume was markedly reduced. In vivo treatment with the MMP inhibitor doxycycline resulted in a significant decrease in the number of lung colonies in both genotypes, but the tumors that formed were bigger and more vascularized. Increased tumor vascularization paralleled decreased plasma levels of MMP9 and consequent decreased angiostatin synthesis. These results demonstrate that while inhibition of MMPs prevents and/or reduces tumor invasion and lung metastasis, it has the paradoxical effect of increasing the size and vascularization of metastatic tumors due to decreased generation of inhibitors of endothelial cell proliferation. The continued growth of these large well-vascularized tumors may explain the poor efficacy of MMP inhibitors in lung cancer clinical trials.
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PMID:Increased plasma MMP9 in integrin alpha1-null mice enhances lung metastasis of colon carcinoma cells. 1575 90

The role of matrix metalloproteinase (MMP)9 in lung cancer progression is controversial. MMP9 promotes local tumor progression and distant metastasis in mouse models by enhancing extracellular matrix degradation, releasing VEGF from extracellular matrix and promoting vascular pericyte recruitment. Furthermore, increased plasma MMP9 expression levels in human subjects with metastatic non-small cell lung cancer (NSCLC) inversely correlates with survival. In contrast, MMP9 can benefit the host by generating inhibitors of endothelial cell proliferation such as angiostatin and NC1 domains of collagen IV. To better understand the role of host MMP9 on the primary growth and metastatic potential of NSCLC, we performed an orthotopic model of NSLC in integrin alpha1-null mice (a genetic model for increased MMP9). In these mice we observed decreased number, size and vascularization of primary NSCLC tumors when compared to wild type controls. In addition, decreased number and size of NSCLC-derived metastases were evident in the alpha1-null mice. Furthermore, pharmacological inhibition of MMPs in the alpha1-null mice at the time of tumor cell injection resulted in an increase in the number of both primary and metastatic lung cancer as compared to untreated mice, suggesting that primary growth and metastases of NSCLC are worsened by the early inhibition of MMPs. In conclusion, although MMP9 may potentially promote tumor growth and metastasis, production of MMP-dependent anti-angiogenic factors seems to override these effects and protects the host from NSCL growth and progression.
Clin Exp Metastasis 2005
PMID:An orthotopic model of lung cancer to analyze primary and metastatic NSCLC growth in integrin alpha1-null mice. 1608 39

In order to study the expression of MMP2, MMP3 and MMP9 in breast cancer brain metastasis, we used a syngeneic rat model of distant metastasis of ENU1564, a carcinogen-induced mammary adenocarcinoma cell line. At six weeks post inoculation we observed development of micro-metastasis in the brain. Immunohistochemistry and Western Blotting analyses showed that MMP-2, -3 and -9 proteins expressions are consistently significantly higher in neoplastic brain tissue compared to normal brain tissue. These results were confirmed by RT-PCR. In situ zymography revealed gelatinase activity within the brain metastasis. Gel zymography showed increase in MMP2 and MMP3 activity in brain metastasis. Furthermore, we were able to significantly decrease the development of breast cancer brain metastasis in animals by treatment with PD 166793, a selective synthetic MMP inhibitor. In addition, PD 166793 decreased the in vitro invasive cell behavior of ENU1546. Together our results suggest that MMP-2, -3 and -9 may be involved in the process of metastasis of breast cancer to the brain.
Clin Exp Metastasis 2005
PMID:Expression of MMP2, MMP9 and MMP3 in breast cancer brain metastasis in a rat model. 1615 51

The Runx2 (Cbfa1/AML3) transcription factor and matrix metalloproteinase 9 (MMP9) are key regulators of growth plate maturation and bone formation. The genes for both proteins are characteristic markers of breast and prostate cancer cells that metastasize to bone. Here we experimentally addressed the compelling question of whether Runx2 and MMP are functionally linked. By cDNA expression array analysis, we identified MMP9 as a novel downstream target of Runx2. Like that of MMP13, MMP9 expression is nearly depleted in Runx2 mutant mice. Chromatin immunoprecipitation and electrophoretic mobility shift assays revealed the recruitment of Runx2 to the MMP9 promoter. We show by mutational analysis that the Runx2 site mediates transactivation of the MMP9 promoter in osteoblasts (MC3T3-E1) and nonosseous (HeLa) cells. The overexpression of Runx2 by adenovirus delivery in nonmetastatic (MCF-7) and metastatic breast (MDA-MB-231) and prostate (PC3) cancer cell lines significantly increases the endogenous levels of MMP9. The knockdown of Runx2 by RNA interference decreases MMP9 expression, as well as that of other Runx2 target genes, including the genes for MMP13 and vascular endothelial growth factor. Importantly, we have demonstrated using a cell invasion assay that Runx2-regulated MMP9 levels are functionally related to the invasion properties of cancer cells. These results are consistent with Runx2 control of multiple genes that contribute to the metastatic properties of cancer cells and their activity in the bone microenvironment.
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PMID:The Runx2 osteogenic transcription factor regulates matrix metalloproteinase 9 in bone metastatic cancer cells and controls cell invasion. 1616 39

Rearrangements of the RET receptor tyrosine kinase gene generating RET/PTC oncogenes are specific to papillary thyroid carcinoma (PTC), the most frequent thyroid tumor. Here, we show that the RET/PTC1 oncogene, when exogenously expressed in primary normal human thyrocytes, induces the expression of a large set of genes involved in inflammation and tumor invasion, including those encoding chemokines (CCL2, CCL20, CXCL8, and CXCL12), chemokine receptors (CXCR4), cytokines (IL1B, CSF-1, GM-CSF, and G-CSF), matrix-degrading enzymes (metalloproteases and urokinase-type plasminogen activator and its receptor), and adhesion molecules (L-selectin). This effect is strictly dependent on the presence of the RET/PTC1 Tyr-451 (corresponding to RET Tyr-1062 multidocking site). Selected relevant genes (CCL20, CCL2, CXCL8, CXCR4, L-selectin, GM-CSF, IL1B, MMP9, UPA, and SPP1/OPN) were found up-regulated also in clinical samples of PTC, particularly those characterized by RET/PTC activation, local extrathyroid spread, and lymph node metastases, when compared with normal thyroid tissue or follicular thyroid carcinoma. These results, demonstrating that the RET/PTC1 oncogene activates a proinflammatory program, provide a direct link between a transforming human oncogene, inflammation, and malignant behavior.
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PMID:Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene. 1620 90

Gastric endocrine tumours (gastric carcinoids) usually grow from enterochromaffin-like (ECL) cells. Three types of tumour may be distinguished on the basis of the background gastric pathology: type I, which develops in atrophic body gastritis (ABG); type II, which is associated with multiple endocrine neoplasia and Zollinger-Ellison syndrome; and the sporadic type III, which is not associated with any background pathology. This classification plays a major role in determining the optimal approach to these diseases. In fact, type I carcinoids can be considered to be benign lesions, with exceptional risk of metastases. Type II, in contrast, may be associated with distant metastases, which are also common in type III carcinoids. The therapeutic approach is based mainly on endoscopic excision and somatostatin analogues in types I and II, or on surgical resection in type III. Both types I and II grow under the stimulus of hypergastrinaemia through a well-described sequence. However, gastrin is sufficient to cause ECL cell hyperplasia and dysplasia, but not transformation, which is due to menin defects in MEN-I patients, or to other unknown alterations in ABG. Several other candidates--including Bcl2, p53 and MMP9--have been linked with carcinoid initiation and progression. The biology of type III tumours which are not associated with hypergastrinaemia is still poorly understood.
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PMID:Endocrine tumours of the stomach. 1625 92

Matrix metalloproteinases (MMPs), in particular the gelatinases MMP2 and MMP9, are important mediators of tumour invasion and metastasis. We examined whether plasma gelatinase levels could predict lymph node metastasis in breast cancer patients. Further, we investigated the relationship of plasma gelatinase levels with Her2/neu expression, recently acknowledged as an important prognostic factor for recurrence, and with various clinicopathological factors. Preoperative plasma samples from 81 breast cancer patients were collected. Total and active gelatinase levels were measured by enzyme immunoassays and activity assays, respectively. Neither total nor active plasma MMP2 levels correlated with nodal status or with any of the classical clinicopathological factors including histological tumour type, tumour size and grade and hormone receptor status. Patients with Her2/neu overexpressing tumours showed an increase of 27% (P=0.007) in plasma MMP2 activity, but not in total MMP2, compared with patients without overexpression. MMP9 levels, total and active, did not correlate with any of the investigated variables. In contrast to MMP9, total MMP2 levels correlated significantly with active MMP2 levels. In summary, total and active plasma gelatinase levels failed to identify high risk for axillary lymph node metastasis. Active plasma MMP2 was significantly increased in patients with Her2/neu overexpressing tumours, suggesting a role for Her2/neu in the signalling pathways of MMP2 activation in carcinogenesis. However, this increase was too small to be of clinical use. Furthermore, no relationship was found between plasma gelatinase levels, total or active, and any of the clinicopathological prognostic factors.
Clin Exp Metastasis 2005
PMID:Plasma gelatinase levels in patients with primary breast cancer in relation to axillary lymph node status, Her2/neu expression and other clinicopathological variables. 1632 Jan 12


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